Efficient and practical synthesis of Mannich bases related to gramine mediated by zinc chloride

Article abstract of DOI:10.1080/00397910600602503

An efficient and practical procedure for the Mannich reaction of secondary amine, formaldehyde, and indole or N-methylindole employing zinc chloride is presented. A series of gramine derivatives were obtained in 58-98% yields at room temperature in EtOH by using this method. Copyright Taylor & Francis Group, LLC.

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Efficient and Practical Synthesis of Mannich
Bases Related to Gramine Mediated by Zinc
Chloride
Hong‐Guang Dai a , Ji‐Tai Li a & Tong‐Shuang Li a
a College of Chemistry and Environmental Science, Hebei University, Key
Laboratory of Analytical Science and Technology of Hebei Province, Baoding,
China
Version of record first published: 18 Aug 2006.
To cite this article: Hong‐Guang Dai , Ji‐Tai Li & Tong‐Shuang Li (2006): Efficient and Practical Synthesis of
Mannich Bases Related to Gramine Mediated by Zinc Chloride, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 36:13, 1829-1835
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Synthetic Communicationsw, 36: 1829–1835, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600602503
Efficient and Practical Synthesis of Mannich
Bases Related to Gramine Mediated
by Zinc Chloride
Hong-Guang Dai, Ji-Tai Li, and Tong-Shuang Li
College of Chemistry and Environmental Science, Hebei University,
Key Laboratory of Analytical Science and Technology of Hebei
Province, Baoding, China
Abstract: An efficient and practical procedure for the Mannich reaction of secondary
amine, formaldehyde, and indole or N-methylindole employing zinc chloride is
presented. A series of gramine derivatives were obtained in 58–98% yields at room
temperature in EtOH by using this method.
Keywords: Gramine, Mannich reaction, synthesis, zinc chloride
INTRODUCTION
Because of the potent biological activity exhibited by various indole deriva-
tives,[1] the investigation of the chemistry of indoles has been and continues
to be one of the most active areas of heterocyclic chemistry.[2] The
Mannich reaction as a powerful carbon–carbon bond-formation process has
wide application for the preparation of diverse aminoalkyl derivatives. In
fact, 3-aminomethylindoles are particularly interesting on account of their bio-
logical activity and use in the total synthesis of ergot alkaloids.[3] Gramine,
which occurs in sprouting barley, is a typical and simple indole alkaloid.
3-(Dimethylaminomethyl)indole is used for the synthesis of tryptophane or
indole-3-acetic acid.
Received in Japan October 9, 2005
Address correspondence to Ji-Tai Li, College of Chemistry and Environmental
Science, Hebei University , Hezuo Road No. 88, Baoding 071002, China. Fax: þ86-
312-5079628; E-mail: lijitai@mail.hbu.edu.cn
1829

1830
H.-G. Dai, J.-T. Li, and T.-S. Li
Many synthetic methods for preparation of Mannich bases related to
gramine have been reported.[4–9] However, in spite of their potential utility,
some of the reported methods suffer from drawbacks such as long reaction
times, low yields, and cumbersome product isolation procedures.
For this reason, a more accessible, convenient, and efficient mediator
system is desirable.
Zinc chloride has been extensively used as a catalyst for many organic
reactions, such as the synthesis of 5-arylidene barbituric acid[10] and Friedel–
Crafts reactions of aromatic compounds. To our knowledge, a Mannich
reaction of secondary amine, formaldehyde, and indole employing zinc
chloride as mediator has not been reported before. In continuation of our
work in synthesis of indole derivatives,[11] we describe zinc chloride as a con-
venient and efficient mediator for the synthesis of Mannich bases related to
gramine via Mannich reaction of secondary amine, formaldehyde, and indole
(Scheme 1).
RESULTS AND DISCUSSION
We studied the influence of the grinding method on the reaction time and
yield. As shown in Table 1, at room temperature, the mixture of HCHO,
HN(CH3)2, 4-CH3C6H4SO3H, and indole was ground by mortar and pestle
for 5 min and indole disappeared (as indicated by TLC), but the yield of
gramine was only 13% and an insoluble polymeric gum was formed. We
ground the mixture of HCHO, HN(CH3)2, 4-CH3C6H4SO3H, and indole in
an icebath for 20 min and then laid the mixture for 64 min at room tempera-
ture, but the yield of gramine was only 33%.
We also examined the influence of the ultrasound irradiation on the
reaction. As shown in Table 1, we found that ultrasound irradiation did not
improve the yield of gramine. For example, the reaction of formaldehyde,
dimethyl amine (3a), and indole gave 3-dimethylaminomethylindole (4a) in
84% yield mediated by Ni(OAc)2 using stirring for 180 min, whereas under
ultrasound irradiation, 4a was obtained in 78% yield within the same time.
As shown in Table 1, the effects of different mediators, such as
4-CH3C6H4SO3H, HCl, H2NSO3H, Ni(OAc)2, Cu(OAc)2, and ZnCl2, were
examined. Among these mediators, ZnCl2 was found to be an excellent
Scheme 1.

Synthesis of Mannich Bases
1831
Table 1. Effects of different conditions on the reaction of dimethylamine,
formaldehyde, and indolea
Amount of
mediator
(%mol)
T
(min)
Yield
(%)b
Entry
Mediator
Method
1c
2d
4-CH3C6H4SO3H
4-CH3C6H4SO3H
4-CH3C6H4SO3H
HCl
100
100
100
100
100
100
100
Grinding
Grinding
U.s.
5
20
13
33
85
82
53
78
84
65
71
82
91
75
81
98
93
3c
120
120
120
180
180
420
150
150
150
90
4c
U.s.
U.s.
5c
H2NSO3H
Ni(OAc)2
Ni(OAc)2
6c
U.s.
7c
Stirring
Stirring
Stirring
Stirring
Stirring
Stirring
Stirring
Stirring
Stirring
8e
9e
Ni(OAc)2
Cu(OAc)2
ZnCl2
100
100
100
50
10e
11e
12e
13e
14e
15e
ZnCl2
ZnCl2
100
150
250
90
90
ZnCl2
ZnCl2
90
aThe reaction was carried out at room temperature.
bIsolated yields.
cThe sequence of adding reagents was formaldehyde, dimethylamine, mediator, indole.
dThe sequence of adding reagents was formaldehyde, dimethylamine, mediator,
indole. Ground the mixture in ice bath for 20 min and then laid the mixture for
64 min at room temperature.
eThe sequence of adding reagents was dimethylamine, mediator, formaldehyde, indole.
mediator in terms of yield and reaction time. So, ZnCl2 was chosen as the
mediator for the synthesis of Mannich bases related to gramine.
We studied the effect of the amount of the mediator on the reaction yield.
As shown in Table 1, as the amount of ZnCl2 increased, the reaction yields
were improved. For example, when the amount of the mediator was 50%
mol, the yield was 75% within 90 min, whereas when using 150% mol, the
reaction needed only 90 min to give gramine in 98% yield.
From the results in Table1, thereactionconditions we chose were as follows:
secondary amine (3, 2mmol), ZnCl2 (3 mmol), formaldehyde (2, 2mmol), and
indole (1, 2 mmol). Using this reaction condition, we did a series of experiments
for reactions of secondary amine, formaldehyde, and indole. The results are sum-
marized in Table 2. It is obvious that the synthesis of Mannich bases related to
gramine mediated by ZnCl2 represents a better procedure in terms of higher
yields, milder reaction conditions, and shorter reaction times. For example, 4a
was previously prepared by letting it sit for 10 h catalyzed by acetic acid.[4] The
present procedure gave 4a in 98% yield within 90 min.

1832
H.-G. Dai, J.-T. Li, and T.-S. Li
Table 2. Synthesis of Mannich bases related to gramine mediated by zinc chloride
Isolated
yield
(%)
Mp (8C)
(lit)
Entry
R1
R2
R3
T (min)
90
aa
H
CH3
CH3
98
128–130
(127–128)[4]
109–110
ba
bb
cc
da
ea
ed
fa
H
H
H
H
H
H
CH2CH3
CH2CH3
CH2CH3
CH2CH3
90
120
90
73
85
82
98
79
86
82
58
58
88
84
CH2CH2CH3 CH2CH2CH3
–(CH2)5–
Oil product
165–167
121–123
90
–(CH2CH2OCH2CH2)–
–(CH2CH2OCH2CH2)–
120
150
150
520
600
300
120
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH3
CH2CH3
Oil product
Oil product
Oil product
Oil product
Oil product
ga
ha
ia
CH2CH2CH3 CH2CH2CH3
–(CH2)5–
–(CH2CH2OCH2CH2)–
ja
aThe reaction was carried out at room temperature.
bThe reaction temperature was 2–108C.
cThe reaction temperature was 4–78C.
dThe reaction temperature was 68C.
As shown in Table 2, as far as some reactions are concerned, at lower
temperature the yield increased. The reaction of diethylamine (3b), formal-
dehyde, and indole gave 3-diethyl aminomethylindole (4b) in 73% yield
within 90 min mediated by ZnCl2 at room temperature. However, 4b was
obtained in 85% yield using stirring for 120 min mediated by ZnCl2 at
2–108C. At lower temperature, by-products are difficult to form.
As shown in Table 2, when the amount of the mediator was 150% mol, 4a
was obtained in 98% yield within 90 min, but the reaction of diethylamine,
formaldehyde, and indole gave 4b in only 73% yield within 90 min. It is
apparent that steric hindrance affects the yields.
CONCLUSION
In conclusion, zinc chloride was found to be a convenient and efficient
mediator for the synthesis of Mannich bases related to gramine via Mannich
reaction of secondary amine, formaldehyde, and indole or N-methylindole.
EXPERIMENTAL
Melting points were uncorrected. 1H NMR spectra were measured on a Bruker
Advance 400 (400-MHz) spectrometer using TMS as internal standard and

Synthesis of Mannich Bases
1833
CDCl3 as solvent. Elemental analyses were carried out using Heraeus
analyzer. Sonication was performed on a Shanghai Branson-BUG ultrasonic
cleaner (with a frequency of 25 kHz and a nominal power of 250 W). The
reaction flask was located in the maximum energy area in the cleaner,
where the surface of reactants is slightly lower than the level of the water,
and addition or removal of water was used to control the temperature of the
water bath.
General Procedure
A 50-mL round flask was charged with secondary amine (3, 2 mol), EtOH
(3 mL), zinc chloride (3 mmol), formaldehyde (2, 2 mmol, 36% aq.), and
indole or N-methylindole (1, 2 mmol). The mixture was stirred for a period
as indicated in Table 2. After dilution with H2O (7 mL), the mixture was
made basic with NaOH (6 mmol, 20% aq.) and extracted three times with
ethyl acetate (3 ꢀ 10 mL). Ethyl acetate was evaporated under reduced
pressure. The residue was diluted with H2O (8 mL) and acided with HCl
(4 mmol, 20% aq.). After filtration, the mother liquor was basified with
NaOH (7 mmol, 20% aq.), the resulting suspension was cooled in an ice
bath. The product was collected by filtration and washed with water. If the
product was oil, the product was extracted three times with diethyl ether
(3 ꢀ 10 mL), the combined organic layers were dried over anhyd. MgSO4,
and the solvent was evaporated under reduced pressure. All the products
were confirmed by comparing their melting points, element analyses,
1H NMR data with data reported in literature.
Data
1
Compound 4b. Mp 109–1108C. H NMR (400 MHz, CDCl3): dH ¼ 1.118
(t, 6H, J ¼ 7.2 Hz), 2.599 (q, 4H, J ¼ 7.2 Hz), 3.825 (s, 2H), 7.137–7.207
(m, 3H), 7.378 (d, 1H, J ¼ 8.0 Hz), 7.756 (d, 1H, J ¼ 8.0 Hz), 8.163
(s, 1H). Anal. calcd. for C13H18N2: C, 77.184; H, 8.968; N, 13.848. Found:
C, 77.341; H, 8.958; N, 13.974.
Compound 4c. Oil product. 1H NMR (400 MHz, CDCl3): dH ¼ 1.036 (t, 6H,
J ¼ 7.2 Hz), 1.738 (sextet, 4H, J ¼ 7.2 Hz), 2.634 (t, 4H, J ¼ 7.6 Hz), 3.977
(s, 2H), 7.063 (s, 1H), 7.265–7.361 (m, 3H), 7.904 (d, 1H, J ¼ 7.6 Hz),
8.743 (s, 1H). Anal. calcd. for C15H22N2: C, 78.213; H, 9.626; N, 12.161.
Found: C, 78.066; H, 9.705; N, 12.281.
1
Compound 4d. Mp 165–1678C. H NMR (400 MHz, CDCl3): dH ¼ 1.445
(d, 2H, J ¼ 4.8 Hz), 1.607 (qui, 4H, J ¼ 5.6 Hz), 2.511 (s, 4H), 3.745
(s, 2H), 7.112–7.228 (m, 3H), 7.352 (d, 1H, J ¼ 8.0 Hz), 7.758 (d, 1H,
J ¼ 8.0 Hz), 8.482 (s, 1H). Anal. calcd. for C14H18N2: C, 78.463; H, 8.465;
N, 13.072. Found: C, 78.676; H, 8.473; N, 13.233.

1834
H.-G. Dai, J.-T. Li, and T.-S. Li
1
Compound 4e. Mp 121–1238C. H NMR (400 MHz, CDCl3): dH ¼ 2.540
(s, 4H), 3.727 (s, 2H), 3.743 (s, 4H), 7.145–7.249 (m, 3H), 7.379 (d, 1H,
J ¼ 8.0 Hz), 7.791 (d, 1H, J ¼ 7.6 Hz), 8.207 (s, 1H). Anal. calcd. for
C13H16N2O: C, 72.194; H, 7.456; N, 12.953. Found: C, 72.243; H, 7.480;
N, 13.007.
Compound 4f. Oil product. 1H NMR (400 MHz, CDCl3): dH ¼ 2.492 (s, 6H),
3.641 (s, 3H), 3.813 (s, 2H), 7.011 (s, 1H), 7.358–7.449 (m, 3H), 7.972–7.993
(m, 1H). Anal. calcd. for C12H16N2: C, 76.555; H, 8.565; N, 14.880. Found: C,
76.406; H, 8.589; N, 14.932.
Compound 4g. Oil product. 1H NMR (400 MHz, CDCl3): dH ¼ 1.180 (t, 6H,
J ¼ 7.2 Hz), 2.647 (q, 4H, J ¼ 7.2 Hz), 3.803 (s, 3H), 3.865 (s, 2H), 7.052
(s, 1H), 7.193 (t, 1H, J ¼ 7.2 Hz), 7.297 (t, 1H, J ¼ 7.2 Hz), 7.356 (d, 1H,
J ¼ 8.0 Hz), 7.808 (d, 1H, J ¼ 8.0 Hz). Anal. calcd. for C14H20N2: C,
77.732; H, 9.318; N, 12.950. Found: C, 77.806; H, 9.364; N, 12.815.
Compound 4h. Oil product. 1H NMR (400 MHz, CDCl3): dH ¼ 0.978 (t, 6H,
J ¼ 7.2 Hz), 1.649 (sextet, 4H, J ¼ 7.2 Hz), 2.525 (t, 4H, J ¼ 7.2 Hz), 3.816
(s, 3H), 3.869 (s, 2H), 7.048 (s, 1H), 7.202 (t, 1H, J ¼ 7.6 Hz), 7.310 (t, 1H,
J ¼ 8.0 Hz), 7.367 (d, 1H, J ¼ 8.0 Hz), 7.825 (d, 1H, J ¼ 7.6 Hz). Anal.
calcd. for C16H24N2: C, 78.638; H, 9.898; N, 11.463. Found: C, 78.811; H,
9.917; N, 11.667.
Compound 4i. Oil product. 1H NMR (400 MHz, CDCl3): dH ¼ 1.558 (d, 2H,
J ¼ 4.4 Hz), 1.722 (t, 4H, J ¼ 5.2 Hz), 2.600 (s, 4H), 3.819 (s, 5H), 7.105
(s, 1H), 7.259 (t, 1H, J ¼ 8.0 Hz), 7.314–7.409 (m, 2H), 7.865 (d, 1H,
J ¼ 7.6 Hz). Anal. calcd. for C15H20N2: C, 78.903; H, 8.828; N, 12.269.
Found: C, 78.795; H, 8.820; N, 12.384.
Compound 4j. Oil product. 1H NMR (400 MHz, CDCl3): dH ¼ 2.597 (s, 4H),
3.788 (s, 3H), 3.807 (s, 6H), 7.072 (s, 1H), 7.236 (t, 1H, J ¼ 7.2 Hz), 7.315–
7.391 (m, 2H), 7.846 (d, 1H, J ¼ 8.0 Hz). Anal. calcd. for C14H18N2O: C,
73.012; H, 7.877; N, 12.164. Found: C, 73.212; H, 7.964; N, 12.320.
ACKNOWLEDGMENTS
The project was supported by Educational Ministry of China and Natural
Science Foundation of Hebei Province (-B20006000969-), China.
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Synthesis of Mannich Bases
1835
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